3-aminoether pregnanes



States 3,169,132 S-AMINOETHER PREGNANES Robert D. Birkenmeyer, Daniel Lednicer, and Fred Kagan,

Kalamazoo, and Barney J. Magerlein, Portage Township, Kalamazoo County, Mich, assignors to The Up john Company, Kalamazoo, Mich, a corporation of 7 Delaware No Drawing. Filed Apr. 7,'1%1, Ser. No. 101,379

7 14 (Jlaims. (Cl. 260-3973) This invention relates to new steroid compounds and is particularly concerned with 3-aminoethers of the pregnane.

series having the formulae:

N- oni)n o- E R v wherein n has a value of 2 to 3, inclusive, wherein R is selected from the group consisting of H ck /CH2CH O\ H O mo V om-H2 E}C-CH3 CHCH3 v Hg0\ N and /N HgC-C ri -CH wherein R =selected from the group consisting of ketonic oxygen and=NOH and wherein R is selected from the group consisting of i n 1 H n m! I I no Furthermore, the invention relates to the N-oxides of atent 3,169,132 Patented Feb. 9, 1965 aminoethers of 3-hydroxy-20-ketopregnanes with hydroxylamine mineral acid salt in the presence of a base such as potassium or sodium hydroxides or acetates, pyridine, piperidine, alkylpyridines and the like.

The aminoether, obtained in the form of a salt, can be converted to the free aminoether by treatment with a base, and can be, if desired, converted to the salts of other acids by treating the free aminoether base with such acids.

The compounds produced by these reactions have hypocholesteremic activity. The compounds are thus useful in the treatment of atherosclerosis which is a form of arteriosclerosis which is characterized by the fatty degeneration occurring in the arterial walls, by mechanisms not yet definitely established. Hypercholesteremia refers essentially to an excess of cholesterol in the blood serum. While the causes of hypercholesteremia and the nature of its role in atherosclerosis and relation conditions is not clearly understood, considerable'effort has been directed toward reducing blood and tissue cholesterol levels as an attack upon the clinical conditions in which high levels are implicated. It has long been recognized that certain substances such as sitosterol, corn oil, and nicotinic acid are capable of reducing in small degree the blood and tissue cholesterol contents, either by interfering with the absorption of exogenous cholesterol introduced with food, or by facilitating the excretion of cholesterol from the body. Major emphasis, however, has been placed on the search for compounds which will interefere with the production of endogenous cholesterol by the liver and hence oifer a more positive means of control of cholesterol levels.

The novelcompounds of the present application significantly reduce the cholesterol content of both blood and tissue by partially arresting the biosynthesis of cholesterol in the body.

The new compounds, especially in their hydrochloric acid salt form, are also active against parasite-produced diseases in animals. They are particularly active against species'of Trypanosoma, such as T rypanosoma equiperdam and Trichomonas such as Trichomonas vaginalis, Entamoeba histolytica, Entamoeba coli and against many of the eggs and larvae of common animal parasites. The novel materials, therefore, can be used against T richomonas vaginalis, incorporated into suppositories or bougies, or can be used in sprays and as powders, in animal bedding, for cattle or poultry in order to prevent parasitic diseases.

The new compounds also act on the central nervous 7 system, reducing motor-activity and are thus useful as tranquilizers for caged animals or animals in transport.

1 In carrying out the-process of the present invention, the selected starting materials, ZO-ketopregnanes or S- regnenes, are dissoloved in an organic solvent and reacted with the selected di-N-substituted aminoalkyl chloride. The reaction is carried out in the presence of an alkali metal metathetically active reagent, such as triphenylmethyl lithium, sodium or potassium; metal hydrides such as sodium or potassium hydride or an alkyl alkali metal compound such as propyl or butyl lithium or propyl or butyl sodium.

The amount of the di-N-substituted aminoalkyl chloride used in this reaction is preferably in excess of one mole (plus 5 to 50%) per mole of steroid. The base alkali metal metathetically acting reagent is used in a ratio of 1.1 moles of base per mole of steroid. These quantities, however, are not critical and larger amounts can be used.

The ketal derivative which is used in the preferred embodiment ofthis reaction is usually produced by reacting the 20-keto steroid with glycols, wherein the total number of carbon atoms is up to 8, inclusive, and wherein the hydroxyl groups are on carbon atoms separated at the most by one methylene group.

The reaction mixture for the etherification is usually ZO-ketals of 3-hydroxykept at reflux temperature, that is depending on the solvent between 60 and 120 C., and the period of reflux is usually about 2 to 24 hours. After the reaction is terminated, the product is recovered by conventional methods, that is by extraction, recrystallization or chromatography with organic solvents. Since the tertiary amino compound is easily converted to its hydrochloride, in which form it is water-soluble, it is usually extracted from the reaction mixture with aqueous hydrochloric acid. Ether can be added to the reaction mixture for better results in the extraction. Since the free amino base is found to be usually a viscous oil rather than crystalline material, the product is generally used in the form of its hydrochloric acid or sulfuric acid salts.

If 20-oximes are desired the selected 3-aminoether of a ZO-keto pregnane or pregnene is treated with either hydroxylamine or its mineral acid salt such as hydroxylamine hydrochloride or hydroxylamine sulfate in a suitable solvent such'as an alkanol, for example, methanol, ethanol, propanol, isopropanol, butanol or a tertiary amine for example pyridine, collidine, N,N-dimethylaniline and the like or preferably an alcohol in the presence of a base reagent such as tertiary amine, sodium or potassium hydroxides, carbonates or acetates to give the corresponding 20-isonitroso steroid. This process is broadly referred to as oximation. An excess of hydroxylamine salt, usually from 1.1 to molar equivalents per mole of steroid is preferably employed. The pre ferred hydroxylamine mineral acid salt is hydroxylarnine hydrochloride. Alternatively, hydroxylamine itself can be used in place of the hydroxylamine salt and base.

The reaction is preferably'carried out at 20 to 120 degrees centigrade and conveniently at the reflux temperature of the reaction mixture. Under this condition the reaction time is usually from minutes to 48 hours. Both higher and lower temperatures and shorter and longer reaction times are operative. The lower temperature usually requires a correspondingly longer reaction.

The reaction product thus obtained can be isolated from the reaction mixture by conventional methods for example, separating undissolved inorganic material from the solution through filtration of the reaction mixture when in an organic solvent, and thereupon evaporating the filtrate, to obtain the nitroso steroid. Alternatively, the reaction mixture may be poured into water and the resultant precipitate (the nitroso steroid) separated by filtration. Additional purification of the product can be acornplished by conventional methods, for example, by

ene chloride-Skellysolve B (hexanes) and the like.

The 3-aminoether pregnanes or pregnenes, obtained in these reactions can be subjected to additional reactions known in the art, such as:

(1) Reduction of the ll-keto group by lithium aluminnm hydride to give the llfi-hydroxy group. I

(2) Reduction of the ll-keto group by sodium metal in propanol to give the lla-hydroxy group.

(3) Converting the B-aminoether pregnanes or pregnenes when in the salt form (usually hydrochlorides) to the free base by treating these salts with a base, e.g., sodium or potassium carbonate, bicarbonate or dilute solution of sodium or potassium hydroxide to obtain the free base.

(4) Conversion of 3-aminoether pregnanes or pregnenes to the amine salts by treating the free base with a mineral acid such as hydrochloric, sulfuric, hydrobromic, hydroiodic acid or organic acids such as acetic, trimethylacetic, propionic, butyric, Valerie, benzoic or lauric acid and the like.

PREPARATION 1 3a-lzydr0xy-5a-pregnane-20-one ZO-ethylene ketal A mixture of 5 grams of 3a-hydroXy-Sa-pregnane-ZO- one, ten milliliters of ethylene glycol, 0.5 gram of ptoluene-sulfonic acid, and 300 milliliters of benzene was refluxed for 4 hours. The water formed in this reaction was removed by codistillation with benzene. The benzene solution was washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue. This residue was twice recrystallized from ethyl acetate-hexanes to give 3a-hydroxy-5a-pregnane-ZO-one 20-ethylene ketal.

In the same manner given in preparation 1, by reacting the corresponding ZO ketOpregnanes and 20-ketopregnenes with ethylene glycol or other alkylene-1,2-; 2,3-; 1,3-; or 2,4-diols in the presence of an acid catalyst results in the corresponding ketal of the 20-ketopregnane or 20-keto-5-pregnene. Representative ZO-ketals thus obtained include:

3a-hydroxy-5e-pregnane-20-one 20-ethylene ketal 3,8-hydroxy-5a-pregnane-20-one 20-ethylene ketal 3,B-hydroxy-S,B-pregnane-ZO-one 20-ethylene ketal 3a-hydroxy-5/3-pregnane-11,20-dione 20-ethylene ketal BB-hydroXy-Sa-pregnane-I1,20-di0ne 20-ethylene ketal ll-ketopregnenolone 20-ethylene ketal and the like EXAMPLE 1 3,8-(2-diethylamin0ezh0xy)-5-pregnen-20-0ne hydrochloride To a solution of 10 grams of pregnenolone 20-ketal, in 300 milliliters of ether, there was added 1.6 grams of 52.4% dispersion of sodium hydride in oil. The mixture was heated under reflux for five hours. At the end of this time there was added 10 milliliters of a 1:1 by weight mixture of B-diethylaminoethyl chloride and toluene. The suspension was refluxed for a period of 18 hours. After cooling, the suspension was Washed with water, then with 750 milliliters of 0.5 normal hydrochloric acid. The acid washes were allowed to stand for 24 hours at room temperature and then extracted with methylene chloride. The residue, obtained by evaporation of the methylene chloride extracts to dryness, was recrystallized four times from ethyl acetate to yield 1.67 grams of 35- (2-diethylaminoethoxy)-5-pregnen-20-one hydrochloride.

The infrared spectrum of 3B-(Z-diethylaminoethoxy)-5- pregnen-20-one hydrochloride showed that some solvation (hydrate) occurred.

Analysis.Calcd. for C H ClNO /2H O5 C, 70.33; H, 1027; N, 3.04. Found: C, 70.65; H, 10.26; N, 3.42.

EXAMPLE 2 3a-(Z-diethylaminoethoxy Jfi-pregriane-l 1,20-dione hydrochloride A mixture of 5.3 grams (0.015 mole) of 3a-hydroxy,

5fi-pregnane-l1,20-dione 20-ketal and 0.173 gram (0.016 mole) of sodium hydride dispersion in oil (52.4%) and 75 milliliters of benzene was stirred under reflux for 20 hours. After cooling, 4.1 grams of a 1:1 by weight mixture of diethylaminoethyl chloride and toluene was added. After an additional 24 hours of heating ether was added and the organic layer containing 3oc- (Z-diethylaminoethoxy)-5fl-pregnane-11,20-dione 20-ethylene ketal washed to neutrality. The base was extracted with 250 milliliters of 0.5 normal hydrochloric acid and this solution washed with methylene chloride. The amorphous solid which remained when the solvent, methylene chloride, was re moved was allowed to stand for 18 hours with 50 milli-v liters of 2 normal aqueous hydrochloric acid. This solu-v tion was then diluted with 50 milliliters of water and extracted with methylene chloride. The methylene chloride solution was evaporated and the thus-obtained residue recrystallized twice from ethyl acetate: methylene chloride to give 2.84 grams of 3a-(Z-diethylaminoethoxy)-5,8- pregnan-11,20-dione hydrochloride of melting point 192; to 194.

'5 EXAMPLE 3 36-(S-diethylaminopropoxy)-5-pregnene-20-one hydrochloride In the same manner given in Example 1, pregnenolone ZO-ketal was heated with potassium hydride and thereupon treated withdiethylaminopropyl chloride to give 3B-(3-diethylaminopropoxy) p'regnene-20-one hydrochloride.

EXAMPLE 4 3,8- (Z-dimethylizminoethoxy -5-pregnen-20-one hydrochloride In the same manner given in Example 1, pregnenolone 20-ketal was heated with potassium hydride and thereupon treated with dimethylaminoethyl chloride to give 35-(Z-dirnethylaminoethoxy) 5 pregnen-ZO-one hydrochloride.

EXAMPLE 6 3,8-(2-m0rpholinylethoxy)-5-pregnen-20-one hydrochloride In the same manner given in Example 1, pregnenolone 20-ketal was heated with potassium hydride and thereupon treated with morpholinylethyl chloride to give 35- (Z-morpholinylethoxy) -5-pregnen-20-one hydrochloride.

EXAMPLE 7 3 ?-(Z-piperidinylethoxy)-5-pregnen-20-one hydrochloride In the same manner given in Example 1, pregnenolone ZO-ketal was heated with potassium hydride and thereupon treated with piperidinylethyl chloride to give 3,6-(2- piperidinylethoxy) -5-pregnen-20-one hydrochloride.

EXAMPLE 8 3fl-(2-pyrrolidinylethoxy -5-pregnen-20-one hydrochloride In the same manner given in Example 1, pregnenolone 20-ketal was heated with potassium hydride and there upon treated with pyrrolidinylethyl chloride to give 3/3-(2- pyrrolidinylethoxy)-5-pregnen-20 one hydrochloride.

EXAMPLE 9 3B-(Z-diethylaminoethoxy)-5-pregnene-1L20-dione hydrochloride In the same manner given in Example 1, ll-ketopregnenolone ZO-ketal is heated with potassium hydride and thereupon treated with diethylaminoethyl chloride to give 35-(Z-diethylaminoethoxy)-5-pregnene-11,20-dione hydrochloride.

EXAMPLE 10 313- (Z-dimethylaminoeihoxy) -5-pregnene-11,20di0ne hydrochloride In the same manner given in Example 1, ll-ketopregnenolone 20-ketal is heated with potassium hydride and thereupon treated with dimethylaminoethyl chloride to give 3 3-(Z-dimethylaminoethoxy)-5-pregnene-11,20-di0ne hydrochloride.

EXAMPLE 11 3,8- (3-dimethylaminopropoxy )5 pregnene-1 1 ,20-dione hydrochloride In the same manner given in Example 1, 11-ketopregnenolone 20-ketal is heated with potassium hydride and 6 thereupon treated with dimethylaminopropyl chloride to give 3;3-(3-dimethylarninopropoxy) 5 pregnene 11,20- dione hydrochloride.

EXAMPLE .12

3B-(S-diethylaminopropoxy)-5-pregnene-11,20-dione hydrochloride In the same manner given in Example 1, ll-ketopregnenolone 20-ketal is heated with potassium hydride and thereupon treated with diethylaminopropyl chloride to give 3 B- 3-diethylaminopropoxy) -5 -pregnene-1 1,20-dione hydrochloride.

EXAMPLE 13 35-(2-morpholinylethoxy)-5-pregnene-11,20-

dione hydrochloride In the same manner given in Example 1, 11-ketopregnenolone ZO-ketal is heated with potassium hydride and thereupon treated with morpholinylethyl chloride to give 3,8-(2-morpholinylethoxy)-5-pregnene-l1,20-dione hydrochloride.

EXAMPLE 14 3,8- (Z-pz'peridinylethoxy) -5-pregnene-l1,20-

dione hydrochloride In the same manner given in Example 1, ll-ketopregnenolone ZO-ketal is heated with potassium hydride and thereupon treated with piperidinylethyl chloride to give 3,8 (2-piperidinylethoxy)-5-pregnene-11,20-dione hydrochloride.

EXAMPLE 15 3 8-(2-pyrrolidinylethoxy)-5-pregnene11,20- dione hydrochloride In the same manner given in Example 1, ll-ketopregnenolone 20-ketal is heated with potassium hydride and thereupon treated with pyrrolidinylethyl chloride to give 35 (2 pyrrolidinylethoxy) 5 pregnene 11,20 dione hydrochloride.

EXAMPLE 16 3 06- (Z-diethylaminoethoxy -5 B-pregnan-ZO-one hydrochloride In the same manner given in Example 2, 3a-hydroxy- 5fi-pregnan20-one 20-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3oc- (Z-diethylaminoethoxy)-SB-pregnan-20- one hydrochloride.

EXAMPLE 17 3:1-(Z-dimethylaminoethoxy)-5 B-pregnan-ZO- one hydrochloride In the same manner given in Example 2, 3a-hydroxy- Sfl-pregnan-ZO-one ZO-ketal is heated with sodium hydride and thereupon treated with dimethylaminoethyl chloride to give 30: (Z-dimethylaminoethoxy)-5B-pregnan-20-one hydrochloride. 4

EXAMPLE 18 30t-(2-morpholinylethoxy)-5fi-pregnan-20-one hydrochloride In the same manner given in Example 2, 3a-hydroxy- 5/3-pregnan-20-one ZO-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 30; (2 morpholinylethoxy)-5B-pregnan-20-one hydrochloride.

EXAMPLE 19 3:1- (Z-pyrrolidinylethoxy -5fl-pregnan-20-one hydrochloride In the same manner given in Example 2, Ba-hYdIOXY- Sb-pregnan-ZO-one ZO-ketal is heated with sodium hydride and thereupon treated with pyrrolidinylethyl chloride to give 3u-(2-pyrrolidinylethoxy)-5,8-pregnan-20-one hydrochloride.

EXAMPLE 20 3 oc- (Z-piperidi riylethoxy -5 S-pregnan-ZO-one hydrochloride In the same manner given in Example 2, 3a-hydroxy- 5fi-pregnan-20-one -ketal is heated with sodium hydride and thereupon treated with piperidinylethyl chloride to give 3w(2-piperidinylethoxy)-5p-pregnan-20-one hydrochloride.

EXAMPLE 21 3,8- (Z-diethylam i noe thoxy -5 a-pregnan-ZO-one hydrochloride In the same manner given in Example 2, 35-hydroxy- 5a-pregnan-20-one ZO-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3,8-(2-diethylaminoethoxy)-5a-pregnan-20-one hydrochloride.

EXAMPLE 22 3p- (2-m0rpholinylethoxy -5 a-pregnan-ZO-one hydrochloride In the same manner given in Example 2, 3fl-hydroxy- 5a-pregnan-20-one 20-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 35 (2 morpholinylethoxy)-5a-pregnan-20-one hydrochloride.

EXAMPLE 23 3 a- (Z-diethylaminoethoxy -5 a-pregndn-ZO-one hydrochloride In the same manner given in Example 2, Sac-hydroxy- 5a-preg nan-20-one 20-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3a (2 diethylaminoethoxy)-5a-pregnan-20-one hydrochloride.

EXAMPLE 24 3a-(2-morpholinylethoxy)-5a-pregnan-20-one hydrochloride In the same manner given in Example 2, 3a-hydroxy- 5wpregnan-20-one 20-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 30c (2 morpholinylethoxy)-5a-pregnan-20-one hydrochloride.

EXAMPLE 25 3f!-(Z-diethylaminoethoxy)JB-pregnan-ZO-one hydrochloride In the same manner given in Example 2, 3B-hydroxy- SIB-pregnan-ZO-one ZO-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3,8-(Z-diethylaminoethoxy)5fl-pregnan-20-one hydrochloride.

EXAMPLE 26 3 3-(Z-morpholinylethoxy)-5fl-pregnan-20-one hydrochloride In the same manner given in Example 2, 3,8-hydroxy- SB-pregnan-ZO-one ZO-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 33 (2 morpholinylethoxy)-5fi-pregnan-20-one hydrochloride.

EXAMPLE 27 3-a- (Z-diethylaminoethoxy JB-pregnane-J 1,20-

dione hydrochloride In the same manner given in Example 2, 3u-hydroxy- SB-pregnane-ILZO-dione ZO-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3u-(2-diethylaminoethoxy)-5,B-pregnane- 11,20-dione hydrochloride.

EXAMPLE 28 31x-(Z-dimethylaminoethoxy -5/3-pregnane-1L20- dione hydrochloride- In the same manner given in Example 2, 3a-hydroxy- SB-pregnane-ILZO-dione ZO-ketal is heated with sodium hydride and thereupon treated with dimethylaminoethyl chloride to give 3a- (2-dimethylaminoethoxy)-5fl-pregnane-ll,20-dione hydrochloride.

EXAMPLE 29 3a-(2-morpholinylethoxy)-5;3-pregnane-11,20-

dione hydrochloride In the same manner given in Example 2, 3a-hydroxy- Sfl-pregnane-ILZO-dione 20-ketal is heated With sodium hydride and thereupon treated with morpholinylethyl chloride to give 3a-(2-morpholinylethoxy)-5,B-pregnane- 11,20-dione hydrochloride.

EXAMPLE 3 0 3a- (Z-piperidinylethoxy -5,8-pregnane-l1,20-

dione hydrochloride In the same manner given in Example 2, 3u-hydroxy- 5/3-pregnane-1L20-dione 20-keta1 is heated with sodium hydride and thereupon treated with piperidinylethyl chloride to give 3oc-(2-piperidinylethoxy)-5;3-pregnane-11,20- dione hydrochloride.

EXAMPLE 31 3:1-(Z-pyrrolidinylethoxy)-5 ,B-pregnane- 11,20-dione hydrochloride In the same manner given in Example 2, 3a-hydroxy- 5B-pregnane-11,20-dione 20-ketal is heated with sodium hydride and thereupon treated with pyrrolidinylethyl chloride to give 3a-(2-pyrro1idinylethoxy)-5/3-pregnane- 11,20-dione hydrochloride.

EXAMPLE 32 319- (Z-diethylaminoethoxy -5 a-pregnane- 11,20-dione hydrochloride In the same manner given in Example 2, BB-hydroxy- 5a-pregnane-ll,20-dione ZO-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3;?)-(Ldiethylaminoethoxy)-l5a-pregnanel 1 ,ZO-dione hydrochloride.

EXAMPLE 33 3 )3- (2 -morpholiny lethoxy -5 a-pregnane- 11,20-dione hydrochloride In the same manner given in Example 2, 35-hydroxy- 5a-pregnane-l1,20-dione ZO-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 3,8-(2-morpholinylethoxy)-5u-pregnane- 11,20-dione hydrochloride.

EXAMPLE 34 EXA PLE 35 35- (Z-diethy laminoethoxy JB-pregnane- 11,20-dione hydrochloride In the same manner given in Example 2, 3,8-hydroxy- 5B-pregnane-1L20-dione 20-ketal is heated with sodium hydride and thereupon treated with diethylaminoethyl chloride to give 3/3-(2-diethylaminoethoxy)-5fl-pregnane- 11,20-di0ne hydrochloride.

EXAMPLE 36 3 8- (2 -morph0linylethoxy -5fl-pregnane- 11,20-dione hydrochloride In the same manner given in Example 2, 3fi-hydroxy- 5B-pregnane-11,20-di0ne ZO-ketal is heated with sodium hydride and thereupon treated with morpholinylethyl chloride to give 3/3-(2-morpholinylethoxy)-5,B-pregnane- 11,20-dione hydrochloride.

EXAMPLE 37 In the same manner given in Example 1, other hydrochlorides of S-aminoethers of 20-ketals of 3-hydroxypregnanes and 3-hydroxypregnenes can be made by reacting the 20-ketal of a selected S-hydroxypregnane or 3- hydroxypregnene with a selected dialkylaminoalkylchloride, morpholinylalkylchloride, piperidinylalkyl'chloride or pyrrolidinylalkylchloride. S-aminoethers thus obtained comprise:

3f -(3-dimethylarninopropoxy)-5pregnen-20-one hydrochloride;

3,8-(3-morpholinylpropoxy)-5-pregnen-20-one hydrochloride;

3 B-( 3-piperidinylpropoxy) --pregnen-20-one hydrochloride;

3B-(3-pyrrolidinylpropoxy)-5-pregnen-20-one hydrochloride;

Sfi-( S-morpholinylpropoxy) -5-pregnene-1 1,20-dione hydrochloride;

3 9- 3 -piperidinylpropoxy -5-pregnene-1 1,20-dione hydrochloride;

3 B- 3-pyrrolidinylpropoxy) -5 -pregnene-1 1,20-dione hydrochloride; I

3a-(3-diethylaminopropoxy)-5B-pregnan-20-one hydrochloride 3a-(3-morpholinylpropoxy) 55-pregnan-20-one hydrochloride;

31x-(3-pyrrolidinylpropoxy) -5B-pregnan-20-one hydrochloride 3 oc- 3-piperidinylpropoxy) -5 8-pregnan-20-one hydrochloride;

3 B-(Z-dirhethylaminoethoxy) -5 a-pregnan-20-one hydrochloride;

3 B-(3-diethylaminopropoxy) -5 a-pregnan-ZO-One hydrochloride;

3fl-(2-pyrrolidinylethoxy)-5a-pregnan-20-one hydrochloride;

3 ,B-(B-pyrrolidinylpropoXy) -5 a-pregnan-20-one hydrochloride;

3 B-(2-piperidinylethoxy)-5 a-pregnan-20-one hydrochloride;

3/3-(3-piperidinylpropoxy)-5a-pregnan-20=one hydrochloride;

3 a- (Z-dimethylaminoethoxy) -5a-pregnan-20-one hydrochloride;

3a-(3-diethylaminopropoxy)-5a-pregnan-20-one hydrochloride;

3a-(2-pyrrolidinylethoxy)-5a-pregnan-20-one hydrochloride;

3w(3-pyrrolidinylpropoxy) -5or-pregnan-20-one hydrochloride; i

3a-(2-piperidinylethoxy)-5apregnan-20-one hydrochloride;

3 OC- 3-piperidinylpropoxy) -5u-pregnan-20-one hydrochloride;

. 13- (2-dimethylaminoethoxy) -5}9-pregnan-20-one-hydrochloride; I

3 ,8- 3-diethylaminopropoxy) -55-pregnan-20-one hydrochloride;

3fi-(2-pyrrolidinylethoxy) -5,8-pregnan-20-one hydrochloride;

315'-(3-pyrrolidinylpropoxy) -5B-pregnan-20-one hydrochloride;

3 fl-(Z-piperidinylethoxy)-5B-pregnan-20-one hydrochloride;

3B-(3-piperidinylpropoxy) -5fl-pregnan-20-one hydrochloride; a

3 oc- 3-diethylaminopropoxy) -5,8-pregnane-1 1,20-dione hydrochloride;

3 oc- 3-dimethy1aminopropoxy) -5B-pregnane-1 1,20-dione hydrochloride;

3a-(Z-diethylaminoethoxy)-5a-pregnane-11,20-dione hydrochloride;

3OL- 3-morpholinylpropoxy) -5[3-pregnane-1 1,20-dione hydrochloride;

3a-(3-piperidinylpropoxy)-5/3-pregnane-11,20-dione hydrochloride;

3 cc- 3-pyrrolidinylpropoxy) -5fl-pregnane-1 1,20-dione hydrochloride;

3B- 3-diethylaminopropoxy) -5a-pregnane-1 1,20-dione hydrochloride;

3 fl- 3-dirnethylaminopropoxy) -5u-pregnane-1 1,20-dione hydrochloride;

3,8- 3-morpholinylpropoxy) -5u-pregnane-1 1,20-dione hydrochloride;

3(3- 3-piperidinylpropoxy) -5u-pregnane-l 1,20-dione hydrochloride;

35- 3-pyrrolidinylpropoxy) -5a-pregnane-1 1,20-dione hydrochloride;

3/3-(B-diethylaminopropoxy)-5,B-pregnane-l1,20-dione hydrochloride;

3 8-(3-dimethylaminopropoxy)-5B-pregnane-11,20-dione hydrochloride;

3 ,3- 3-morpholinylpropoxy) -5[i-pregnane-1 1,20-dione hydrochloride;

3 p- 3-piperidinylpropoxy) -5 fi-pregnane-l 1,20-dione hydrochloride;

3 fi- 3- pyrrolidinylpropoxy) -5 fi-pregnane-l 1,20-dione hydrochloride.

EXAMPLE 38 30c- (Z-diethylaminoethoxy)-20-is0nitr0s0- 5,8-pregnan-11-one A suspension of 3.46 grams of 3a-(2-diethylaminoethoxy)-5B-pregnane-11,20-dione hydrochloride in water was made basic with solid sodium bicarbonate. The free amine was taken up in ether, the solution dried and the solvent removed in vacuo. The residual oil was dissolved in a mixture of 1.60 grams of pyridine and 30 milliliters of ethanol. Following the addition of 1.40 grams ofhydroxylamine hydrochloride, the mixture was heated on the steam bath for 20 minutes and then allowed to cool. The thus-obtained suspension was then diluted with water and made basic with sodium bicarbonate. The precipitate that formed was taken up in ether and this solution washed to neutrality with water. The solid which remained when the solvent was removed (3.20 grams) was recrystallized several times from aqueous methanol to give 3oc-(2-diethylaminoethoxy)-20-isonitroso-Sfl-pregnan 11 one of melting point 1611'64.

Analysis. Calcd. for C H N O C, 72.60, H, 10.38; N, 6.27. Found: C, 72.58; H, 10.58; N, 6.56.

EXAMPLE 39 3,6- (Z-diethylamz'noethoxy)-20-isonitr0so-5-pregnene In the manner givenin Example 38, two grams of 3,8-(Z-diethylaminoethoxy) 20-isonitroso-5-pregnene hydrochloride was made basic with solid potassium bicarbonate. The mixture was extracted with ether and the ether solution of the free amine dried over anhydrous sodium sulfate and thereupon distilled in vacuo. The residual material was dissolved in 60 milliliters of ethanol and thereto was added five grams of hydroxylamine hydrochloride and 3.5 grams of sodium hydroxide in the presence of 5 milliliters of water. The mixture was heated to reflux for a period of 75 minutes. Thereafter the mixture was allowed to cool to room temperature, poured into 250 milliliters of water and extracted with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous sodium sulfate and evaporated to give a residue which was four times recrystallized from aqueous methanol to give 3,8-(2-diethylaminoethoxy)-20-isonitroso-S-pregnene.

In the same manner given in Examples 38 and 39, other B-aminoethers of 50cand SB-pregnane and S- regnene as produced in Examples 1 to 37 in the form of hydro- 3 {3- (Z-diinethylaminoethoxy -20-i sonitroSo-S-pregnene;

3 ,8- (Z-morpholinylethoxy -20-isonitroso-S-pregnene;

3 Z-piperidinylethoxy -2()-isonitroso-5 -pre gnene;

313- Z-pyrrolidinylethoxy -20-isonitroso-5-pregnene;

3 B- 3 -dimethylaminopropoxy -20-isonitroso-S-pregnene;

3 B- 3-diethylaminopropoxy -20-isonitroso 5-pregnene;

3 B 3-morpholinylpropoxy) -20-isonitroso-S-pregnene;

3 B- Z-piperidinylpropoxy -20-isonitroso-S-pregnene;

3 [3- 3 -pyrrolidinylpropoxy -20-isonitroso-S-pregnene;

3 fi- Z-dimethylaminoethoxy -20-isonitroso-5 -pregnenl l-one;

3/3-(2-morpholinylethoxy)-20-isonitroso-5-pregnen- I 3,B-(3-pyrrolidinylpropoxy)-20-isonitroso-5-pregnen l l-one;

3 a- 2-morphinylaminoethoxy) -20-isonitroso-Sfipregn ane 3 oc- 3 -dimethylaminopropoxy -2 O-isonitroso-Sflpregnane;

3w Z-diethylaminoethoxy) -20-isonitroso-SB-pregnane;

3 B- (2-morphinylaminoethoxy -20-isonitroso-5 apregnane;

3 B- 3-dimethylaminopropoxy -20-isonitroso-5apregnane 3 5- Z-diethylaminoethoxy -20-isonitroso-5a-pregnane;

3 a- (2-morphinylaminoethoxy) -20-isonitroso-5 oz.-

pregnane;

3 oc- (3-di1nethylaminoprop0xy) -20-isonitroso-5apregnane;

3 oc- Z-diethylarninoethoxy -20-isonitroso-5 a-pregnane;

3 [3- 2-morphinylaminoethoxy) -20-isonitroso-5flpregnane;

3 5- 3 -dimethylaminopropoxy) -20-isonitroso-5fipregnane 3 fl- Z-diethylaminoethoxy -20-isonitroso-SB-pregnane;

3 Ot- (Z-dimethylaminoethoxy) -20-isonitroso-SB-pregnan- 1 Lone 3 a- S-diethylaminopropoxy -20-isonitroso-Sfi-pregnanl l-one;

3 oc- 2-morpholinylethoxy -20-isonitroso-Sfi-pregnanl l-one;

3 or- (2-pyrrolidinylethoxy -20-isonitroso-5,6-pregnanl l-one;

3 a- (3 -piperidinylpropoxy -O-isonitroso-5,8-pregnan- 1 l-one;

3 B- Z-dImethylaminoethoxy) -20-isonitroso-Sa-pregnan- 1 l-one;

3p- S-diethylaminopropoxy) -2G-isonitrOsO-Sa-pregnan- 1 l-one;

3 5- (Z-morpholinylethoxy -20-isonitrosoda-pregnan- 1 l-one;

7 l2 3B- 2-pyrroiidinylethoxy) -2 O-isonitroso-S a-pregnanl l-one; i 3 ;3-( 3-piperidinylpropoxy)'20-isoriitroso-5a-pregnan- 1 l-one.

EXAMPLE 40 A 306- (Z-dz'ezhylaminoethoxy l1B-hydr0xy55- pregizan-ZO-one 3a-(Z-diethyiaminoethdxy) 5 8 pregnane-11,20-dione 20-ethylene ketal was prepared as shown in Example 2 by treating 3 zi-hydrOXy-Sdpregnene-l1,20 dione ZO-ketal with sodium hydride in benzene solution and thereupon with diethylaminoethyl chloride. After refluxing this mixture, the organic layer was washed with water until neutral, dried over anhydrous sodium sulfate and evaporated to give crude 3a.-(Z-diethylaminoethoxy)-5fi-pregnane- 11,20-dione ZO-ethylene ketal.

Fifty milliliters of 'tetrahydrofuran containing 5 grams of 3a-(Z-diethylaminoethoxy)-5B-pregnane-1l,20- dione ZO-ethylene ketal was added to a well-stirred suspension of two grams of lithium aluminum hydride in 20 milliliters of tetrahydrofuran. The mixture was heated under reflux with stirring for six hours and was thereupon allowed to cool. Excess reagent was destroyed with ethyl acetate. A hundred milliliters of water and a hundred milliliters of ether were then added. The mixture was shaken and the organic layer separated and washed several times with water. The organic layer was thereupon dried over anhydrous sodium sulfate and then evaporated yielding a solid residue. This residue was taken up in ether and the ether solution extracted with 0.5 N hydrochloric acid. The suspension of the hydrochloride in the aqueous acid was extracted with chloroform and the chloroform extracts combined and evaporated to give a residue. This residue was recrystallized twice from chloroform-ethyl acetate to give 3oz-(2-diethylaminoethoxy)-llfl-hydroxy SB- regnan-ZO-one hydrochloride.

EXAMPLE 41 35- (Z-diethylaminoethoxy 1 fl-hydroxy-S-pregnen- 20-0112 hydrochloride In the same manner given in Example 40, ll-ketopregnenolone ZO-ethylene ketal was prepared by reacting ll-ketopregnenolone ZO-ketal with sodium hydride and thereupon with fi-diethylaminoethyl chloride in benzene solution, heating the thus-obtained mixture for 18 to 24 hours, then cooling the mixture and washing with water and thereupon evaporating the reaction mixture to dryness.

The thus-obtained 3 ,6- (2 diethylaminoethoxy)-11B- hydroxy-5-pregnene-11,20-dione 20-ketal was reduced with lithium aluminum hydride in tetrahydrofuran and the thus-obtained 35-(Z-diethylaminoethoxy) -1 lfl-hydroxy-S- pregnen-ZO-one recovered in the form of its hydrochloride.

In the same manner given in Example 40, other 3-aminoethers of lldhydroxy pregnanes and pregnenes can be made by reducing the corresponding ll,20-dione ZO-ketals with lithium aluminum hydride and subsequently recovering the product as hydrochloride. Representative compounds thus obtained include:

13 309% 2-morpholinylethoxy) -1 1 [3-hydroxy-5e-pregnan-20- one hydrochloride; 3c;- 3-pyrrolidinylpropoxy) -1 IB-hydroxy-SB-pregnan- 20-one hydrochloride; 3 a-(Z-piperidinylethoxy) -l l,B-hydroxy-fi-pregnan 20- one hydrochloride; 3,8-(2-dimethylaminoethoxy) l 1B-hydroxy-5u-pregnan- ZO-one hydrochloride; 3 8- 2-morpholinylethoxy) -l 1 fl-hydroxy-S a-pregnan-ZO- one hydrochloride; 313- 3-pyrrolidinylpropoxy) -1 l ,8-hydroxy-5 a-pregnan-ZO- one hydrochloride; t 313' (Z-piperidinylethoxy) -1 1B-hydroxy-Sa-prgnan-ZO- one hydrochloride.

ExAMPLE 42 3ot(2-diezhy laminoethoxy 1 1 a-hydrOxy-SB pregnan-20-0ne hydrochloride 1 To a solution of 0.5 gram of 3a-(2-diethylamino ethoxy)-5;8-pregnane-l1,20-dione 20'-ketal ,(example 40), in 50 milliliters of normal propyl alcohol at reflux tem perature, is added five grams of sodium in small pieces.

After a period of one hour, methanol is added to tie-1 compose the remaining unreacted sodium. To the reaction mixture is thereupon added 50 milliliters of water and the mixture is distilled until the product separates from it. The crudeproduct is removed from the essentially aqueous medium by filtration and is recrystallized from a mixture of chloroform and ethyl acetate to give pure crystalline 3a-(2-diethylaminoethoxy)-1la-hydroxy- SB-pregnan-ZO-one ZO-ketal.

The ketal was taken up in 0.5 aqueous ethanolic hydrochloric acid and the mixture was allowed to stand over night. It was then diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, dried and evaporated and thethusobtained residue three times recrystallized from ethyl acetate to give 3a-(Z-diethylaminoethoxy)-11a-hydroxy- 5,8-pregnen-20-one hydrochloride. i

In the same manner as shown in Example 42, other 3- aminoethers of lla-hydroxy pregnenes can be made by reducing the corresponding'l1,20-dione pregene 20-ketals with sodium metal and normal propyl alcohol. Treatment of these compounds with hydrochloric acid yields the corresponding hydrochloride. Compounds thus obtained include:

313-(3-diethylaminopropxy) -1 1ot-hydroxy-5-pregnen-20 one hydrochloride; i

313- Z-morpholinylethoxy) -1 1a-hydroxy-5-pregnen-20- one hydrochloride; p

3 8-(Z-pyrrolidinylethoxy)-1la-hydroxy-5-pregnen-20 one hydrochloride;

3 fl-( 2-piperidinylethoxyl-l lix-hydroxy-5-pregnen-20-one hydrochloride; 3 fl-(B-morpholinylpropoxy) -1 1whydroxy-5-pregnen-20- one hydrochloride; 3 8-(3-dimethylaminopropoxy)-l lot-hydroxy-i-pregnen- ZO-one hydrochloride; 3 a-(Z-dimethylarninoethoxy) -1 1ot-hydroxy-5 fu -pregnan- 20-one hydrochloride; 3 a-(2-morpholinylethoxy) -1 1 u-hydroxy-5B-pregnan-2Q- one hydrochloride; 3 oc-( 3-pyrrolidinylpropoxy) -1 Iu-hydrOXy-Sfi-Pregnan- 20-one hydrochloride; 3 a-(2-piperidiny1ethoxy) -1 l a-hydroXy-SB- regnan-ZO- one hydrochloride;

3 u-(2-diethylaminoethoxy) -l lot-hydroxy-i aregn'an-ZO- one hydrochloride;.

3 ,9-( Z-dimethylaminoethoxy) -1 1a-hydroxy-5 tat-pregnan- 20-"one hydrochloride; 7

3 ,B- 2-m or-pholinylethoxy) 1 1oc-hydroxy-5 a-pregnan-ZO- one hydrochloride;

3 fi-(B-pyrrolidinylpropoxy) -1 1a-hydroxy-5a -pregnan-2O- one hydrochloride;

EXAMPLE 43 3a (Z-diethylaminoethoxy -1 1 fi-hydroxy-ZO- isonitroso-5fiapregnane In the same manner given in Example 38, 3a(2-diethylaminoethoxy)-l1fl-hydroxy-Sfl-pregnan-ZO-one hydrochloride was treated first with solid sodium bicarbonate to give the free amine and then with hydroxylamine hydrochloride and pyridine in ethanol solution. Heating the reaction mixture, then diluting with water and adding basic sodium bicarbonate gave a precipitate which was taken up with ether and several times recrystallized to give pure 3a-(2-diethylaminoethoxy)-l lfi-hydroxy-ZO-isonitroso-SB- regnane.

In the same manner given in Example 43, other 3- aminoethers oil 15- and 1lot-llYdt'OXY-ZO-lIlSOIlllZIOSO-Pfg: nanes can be made from the products shown in Examples 40 to 43, inclusive. Representative compounds include: 35 (Z-diethylaminoethoxy)-11fi-hydroxy-ZO-isonitroso- S-pregnene; 3e (Z-diethylaminoethoxy)-l1a-hydroxy-20- isonitroso-S-pregnene; 3a-(2-diethylaminoethoxy)-1 lot-hydroxy-20-isonitroso-5/3-pregnane and the like.

Treatment of the 20-is0nitroso compounds of the foregoing products with hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, propionic acid and the like in alcohol or ether solution gives the corresponding acid salts of these aminoethers. t

, Treatment of any of the salts of 3-aminoethcrs of the beforegoing pregnanes and pregnenes with carbonate or bicarbonates of potassium or sodium, or titrating such salts with sodium hydroxide or potassium hydroxide solution until pinkness to phenolphthaleine gives the 3-aminoethers of the foregoingpregnanes and pregnenes as free bases.

EXAMPLE 44,

3B-(Z-diethylaininoethoxy 5 -pregnen-200ne N -0xide hydrochloride Toa solution of 3,B-(Z-diethylaminoethoriy)-5-pregnen- 20-one hydrochloride (3.2 grams), dissolved in 20 milliliters of methanol, wasadded l0 milliliters of a 5 percent solution of sodium hydroxide in methanol. After swirling for'five minutes the mixture was filtered and the filtrate evaporated to dryness under vacuum. The residue was taken up in milliliters of methylene chloride which was then washed with three 25-milliliter portions of water. The methylene chloride phase. was filtered and then evaporated to dryness under vacuum, yielding the free base of the starting hydrochloride. This white solid material was dissolved in 10 milliliters of ethanol, cooled in an ice bath and five milliliters of 30 percent hydrogen peroxide solution added. After standing at about 25 degrees for 18 hours, the excess, hydrogen peroxide was destroyed by portionwise addition of 500 milligrams of platinum oxidecatalyst. Filtration and evaporation of the obtained filtrate gave a white solid which was dissolved in ether. Hydrogen chloride gas was bubbled into this solution and the white solid which precipitated was collected, dried and recrystallized twice from acetone to give 3fi-(2-diethylaminoethoxy)-5-pregnen-20-one N-oxide hydrochloride.

EXAMPLE 45 3a-(2-diethylaminoeth0xy) -1IB-hydroxy-SB-pregnan- 20-0ne N-0xide hydrochloride To a mixture of 0.38 mole of diethylaminoethyl chloride, dissolved in 250 milliliters of ethanol and cooled in an ice-bath, was added milliliters of 30 percent hydrogen peroxide. After standing at about five degrees for 18 hours, the excess hydrogen peroxide was destroyed by the portionwise addition of platinum oxide catalyst. Af

ter filtration, the solvent was evaporated in vacuo to yield crude diethylaminoethyl chloride N-oxide.

This crude diethylaminoethyl chloride N-oxide was added to a benzene solution of the lithium salt of 30,11iidihydroxy-Sfl-pregnan-ZO-one -ethylene ketal obtained by treating this 20-ethylene ketal in benzene solution with triphenylmethyl lithium. The reaction mixture was heated at reflux for 24 hours, cooled to room temperature, diluted with 1000 milliliters of ether and extracted with three portions of 750 milliliters of hydrochloric acid (one part 37 percent hydrochloric acid and nine parts water). The combined aqueous acidic extracts were washed once with 750 milliliters of ether and then extracted with three SOD-milliliter portions of methylene dichloride. The methylene dichloride extracts were combined, dried, evaporated and the thus-obtained residue twice recrystallized from ethanol to give L-(Z-diethylaminoethoxy)- llfi-hydroxy-S/i-pregnan-20-one N-oxide hydrochloride.

In the same manner given in Example 44, other N-oxide hydrochlorides can be synthesized, such as:

33-(Z-dimethylaminoethoxy)-5-pregnen-20-one N oxide hydrochloride;

35 (3-diethylaminopropoxy)-5-pregnen-20-one N oxide hydrochloride;

3,8 (3-morpholinylpropoxy)-5-pregnen-20-one N oxide hydrochloride;

3 ,8 (3 pyrrolidinylpropoxy)-5-pregnen-20-one N oxide hydrochloride;

3 ,G-(Z-piperidinylethoxy)-5-pregnene-20-one N oxide hydrochloride;

35 (Z-dimethylaminoethoxy)-5-pregnene-11,20-dione N- oxide hydrochloride;

3 fi-(3-diethylaminopropoxy) -5-pregnene-1 1,20 dione N- I oxide hydrochloride;

3;? a (3-rnorpholinylpropoxy)-5-pregnene-11,20-dione N- oxide hydrochloride;

3,8 (3-pyrrolidinylpropoxy)-5-pregnene-l1,20-dione N- oxide hydrochloride;

3 5- 2-piperidiny1ethoxy) -5-pregnene-1 1,20-dione N-oxide hydrochloride;

3a-(Z-dimethylaminoethoxy)-55-pregnan-20-one N-oxide hydrochloride;

3 oc- 3-diethylaminopropoxy) -5fi-pregnan-20-one N-oxide hydrochloride;

3a (2-morpholinylethoxy)-5fl-pregnan-20-one N oxide hydrochloride;

3w(2-piperidinylethoxy)-5B-pregnan-20-one N-oxide hydrochloride;

3 ,8- Z-dimethylaminoethoxy) -5 a-pregnari-ZO-one N-oxid hydrochlor de; I

3 ,8- 3-diethylaminopropoxy) -5a-pregnan-20-one N-oxide hydrochloride;

3/3 (2 morpholinylethoxy)-5a-pregnan-20-one N-oxide hydrochloride;

3 fl-( 2-piperidinylethoxy)-5 a-pregnan-20-one N-0xide hydrochloride;

3 5-( 2-dimethylaminoethoxy)-5 ,8-pregnan-20-one I hydrochloride;

3 ,8- 3-diethylaminopropoxy) -5 fl-pre gnan-ZO-one N-oxide hydrochloride; I

35 (2 morpholinylethoxy) -5/3-pregnan-20-one N-oxide hydrochloride;

Bfl-(Z-piperidinylethoxy)-5B-pregnan-20-one N-oxide hydrochloride;

3ot-(Z-dimethylaminoethoxy)-5a-pregnan-20-one N-oxide hydrochloride; I

3 oc- 3-diethylaminopropoxy) -5a-pregnan-20-one N-oxide hydrochloride;

31x-(2-morpholinylethoxy)-5a-pregnan20 one N-oxide hydrochloride;

N-oxide 3a-(2-piperidinylethoxy)-5a-pregnan 2O one N-oxide hydrochloride;

3a(Z-dimethylaminoethoxy)-5,B-pregnane 11,20 dione xide hy och or de;

3w(S-diethylaminopropoiry)-5;8-pregnane-l1,20-dione I N- oxide hydrochloride; I

3w(2-morpho1inylethoxy)-5fl-pregnane-l1,20 dione N- oxide hydrochloride;

3m-(2-piperidinylethoxy)-5,B-pregnane 11,20 dione N- oxide hydrochloride;

3 ,8- 2-dimethylaminoethoxy) -5 a-pregnane-l 1,20-dione N- oxide hydrochloride;

3,8-(3-diethylaminopropoxy)-5a-pregnane-l1,20-dione N- oxide hydrochloride; I 3,8-(2-morpholinylethoxy)-5a-pregnane-11,20 dione N- oxide hydrochloride; I 3fl-(2-piperidinylethoxy)-5a-pregnane-ll,20 dione N- oxide hydrochloride; 3 8-(Z-dimethylaminoethoxy)-5/3-pregnane-11,20-dione N- oxide hydrochloride; 3,8-(3-diethylaminopropoxy)-5,8-pregnane-l1,20-dione N- oxide hydrochloride; 3B-(2-morpholinylethoxy)-5fl-pregnane 11,20 dione N- oxide hydrochloride; I 3B-(2-piperidinylethoxy)-5fi-pregnane 11,20 dione N- oxide hydrochloride; 311-(Z-dimethylaminoethoxy)-5a-pregnane-l1,20-dione N- oxide hydrochloride; 31x-(3-diethylarninopropoxy)-5a-pregnane-l1,20-dione N- oxide hydrochloride; 3a-(2-morpholinylethoxy)-5a-pregnane-ll,20 dione N- oxide hydrochloride; 3a(Z-piperidinylethoxy)-5a-pregnane 11,20 dione N- oxide hydrochloride.

In the same manner given in Example 45, N-oxides of ll-oxygenated pregnane ethers can be synthesized, such as 30r-(3-pyrrolidinylpropoxy)-1l/i-hydroxy 5,8 pregnan- 20-one N-oxide hydrochloride; 3fi-(2-dimethylarninoethoxy)lLB-hydroxy 5a preguan 20-one N-oxide hydrochloride; 3o-(3-diethylaminopropoxy)-1lfi-hydroxy c pregnan- 20-one N-oxide hydrochloride; 3}??-(2-morpholinylethoxy)-1IB-hydrOXy-Sa-Pregnan 20- one N-oxide hydrochloride; I v I 3 {3-(3-pyrrolidinylpropoxy)-1 1 fi-hydroxy-S u-pregnan 20- one N-oxide hydrochloride; I

3w(2-dirnethylaminoethoxy)-lIu-hydroXy-SB pregnan- ZO-one N-oxide hydrochloride;

3a(3-diethylaminopropoxy)-1la-hydroxy-5/3-pregnan 20- one N-oxide hydrochloride; 3w(2-morpholinylethoxy)-11a-hydroxy-5fi-pregnan 20- one N-oxide hydrochloride; 31x-(3-pyrrolidinylpropoxy)-1la-hydroxy-5 3-pregnan 20- one N-oxide hydrochloride; 35-(Z-dimethylaminoethoxy)-11a-hydroxy-5a pregnan- 20-one N-oxide hydrochloride;

3,B(2-diethylamin0ethylthi0)-5-pregnen-20-dne hydrochloride To a.solution of 72 grams of 3fl-hydroxy-5-pregnen-20- one 20-ethylene ketal in 120 milliliters of pyridine was added 77 grams of p-toluenesulfonyl chloride. .After standing at about 25 degrees centigrade for 18 hours a White precipitate appeared which Was collected and recrystallized from ether to give 3B-hydroxy-5-pregnen-20- one 20-ethylene ketal p-toluenesulfonate.

A solution of 51.5 grams of 3B-hydroxy-5-pregnen-20- one Z-O-ethylene ketal p-toluenesulfonate, 90 grams of thiourea, 500 milliliters of ethyl alcohol and 50- milliliters of pyridene were heated under reflux for 5 hours. The reaction mixture was diluted with water to turbidity and then allowed to cool slowly. The thus-obtained precipitate Was collected, suspended in boiling acetone and filtered. The acetone-insoluble product was recrystallized from alcohol or alcohol-ether to give 35-isothiouronium- 5-pregnen-20-one ZO-ethylene ketal p-toluenesulfonate.

A solution of 6.15 grams of Bfi-isothiouronium-S-pregnen-ZO-one 20 ethylene ketal p-toluenesulfonate and 1.2 grams of sodium hydroxide in 100 milliliters of ethyl alcohol was heated under reflux for about 2 hours. Thirteen milliliters of water was added and heating at reflux continued for 2 hours more. The reaction mixture was poured into ice Water, made acid with 0.5 N hydrochloric acid and stirred at about 25 degrees Centigrade for 5 hours. The precipitate which separated during this acid wash was collected, dried and recrystallized from ethyl acetate or acetone-Skellysolve B to give 3B-mercapto-5-pregnen- 20-one.

A mixture of S-grams of 3,B-mercapto-S-pregnen-Zdone, 1O milliliters of ethylene glycol, 0.5 gram of p-toluenesulfonic acid and 300 milliliters of benzene was refluxed for 4 hours. The water formed in this reaction was removed by codistillation with benzene. The benzene solution was Washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The thus-obtained residue was recrystallized from acetone to give 3/8-mercapto-S-pregnen-ZO-one 20 ethylene ketal.

To a solution of grams of 3fi-mercapto-5-pregnen- -one 2O ethylene ketal in one liter of benzene Was added 1.75 grams of butyl lithium in hexane. The mixture was heated under reflux for fixe hours. At the end of this time there was added 3.5 grams of ,Bfi-diethylaminoethyl chloride. The reaction mixture was refluxed for 18 hours, cooled to about 20 degrees Centigrade and shaken With two SOO-milliliter portions of 0.5 normal hydrochloric acid. The acid washes were combined and extracted with methylene chloride. The residue, obtained by evaporation of the methylene chloride extracts to dryness was recrystallized from ethyl acetate or acetone- Skellysolve B, to yield 3,8-(Z-diethylaminoethylthio)-5- pregnen-ZO-one hydrochloride.

EXAMPLE 47 3,8-(Z-diethylaminoethylthio)-20-isonitroso-S-pregnene An aqueous solution of 4.71 grams of 3fi-(2-diethylaminoethylthio)-A -pregnen-20-one hydrochloride was made basic with solid sodium bicarbonate. The free amine was taken up in either, the solution dried and the solvent evaporated. The residual oil was dissolved in a mixture of 2.16 grams of pyridine and 41 milliliters of ethyl alcohol and 1.9 grams of hydroxylamine hydrochloride added. The mixture was heated on a steam bath for about 30 minutes and allowed to cool to about degrees centigrade. The reaction mixture was diluted 18 with water, made basic with sodium bicarbonate and extracted with ether. The ether extracts were washed with water, dried and the solvent evaporated. The solid residue was recrystallized from aqueous methanol to yield the desired product.

In the same manner given the Example 46, 3fl-(2-diethylaminoethylthio)-5-pregnene-11,20-dione can be prepared which compound can be selectively reduced as shown earlier to give 3B-(Z-diethylaminoethylthio)-11ahydroxy-5-pregnen-20-one hydrochloride and 3fl-(2-diethylamino ethylthio)-11,B-hydroxy-S-pregnen-20-one hydrochloride.

In the same manner given in Example 1, reacting 20- ketals of 3,B-mercapto-5-pregnen-20-one, BQ-mercapto- 1 l/8-hydroxy-5-pregnen-20-one, 3 fl-mercapto-l la-hydroxy- 5-pregnen-20-one or 3fi-mercapto-S-pregnene-l1,2(l-dione withdialkylaminoalkyl halides, N-oxides of dialkylaminoalkyl halides, morpholino-, pyrrolidino-, piperidino-N-alkyl halides and N-oxides thereof gives the corresponding 3-thioethers of such compounds. Representative examples of such compounds include:

3,8 (2-dimethylaminoethylthio)-5-pregnen-20-one hydro- We claim:

1. Steroid compounds selected from the group consisting of compounds of the formulae:

CH3 (i=R1 M 1. l

N-(CH),,O 2 R and CH3 JJ=R1 ij wherein n has a value of 2 to 3, inclusive, wherein N R is selected from the group consisting of H 0\ H5C2\ /OH CHg H,o o1 r,

/N- H2O /N H 0 H50, GEE-CH2 Inc-0H2 19 and CHg-OHg D Hr-CH; wherein R is selected from group consisting of ketonic oxygen and =N-OH and wherein R is selected from the group consisting of I \I 0:6 and l the N-oxides of these compounds, and the mineral acid salts of these compounds.

2. 3,8 (2 diethylaminopropoxy) 11a hydroxy pregnen-ZO-one hydrochloride.

3. 3p (2 diethylaminoethoxy) 11,6 hydroxy 5- pregnen-ZO-one hydrochloride.

4. 30a (2 diethylaminoethoxy) 5/3 pregnane 11, 20-dione hydrochloride.

5. 3a (2 diethylaminoethoxy) 20 isonitroso 55- pregnan-l l-one.

2Q .6. 3,6 (2 diethylaminoethoxy) 5 pregnen 20- one N-oxide hydrochloride.

7. 3;? (dimethylaminoethoxy) 20 isonitroso 5- pregnen-l l-one.

8. a (2 dimethylaminoethoxy) 5,3 pregnan 20- one N-oxide hydrochloride.

9. 3a (2 diethylaminoethoxy) 20 isonitroso 5 3- pregnan-l l-one.

10. 3oz (2 diethylarninoethoxy) 1118 hydroxy 20- isonitroso-SB-pregnane.

11. 30c (2 diethylaminoethoxy) 11 3 hydroxy 5ppregnan-ZO-one N-oxide hydrochloride.

12. (2 dimethylaminoethoxy) 5 pregnene 11, 20-dione N-oxide hydrochloride.

13. 3 3 (2 diethylarninoethylthio) 11,8 hydroXy 5- prcgnen-ZO-one hydrochloride.

14. 3,8 (3 diethylaminopropylthio) 5 pregnene- 11,20-dione N-oxide hydrochloride.

No references cited.

LEWIS GOTTS, Primary Examiner.

i run s'mras rarmr omen Q 1 Tl=Elml ERR-'EQTWN Patent No 3 ,169, 132 v I February 9, 1965 Robert D Birkenmeyer et a1,

It" is hereby certified that error appears in the above numbered patent requiringzcorrection that the said Letters Patent should read as corrected below,

Column 2, line 17,33 for '"fellation" read lr related column 4 line-' 46, for "ClN'O- wlI/QIP'Frea d l /2 line- 47", for "1027" read l0 27 column. 5, line 71, for "(3-dimethylaminopropoxy)5", in italics, read (3-dimethylaminopropoxy),5 in italics; column 6, line 72 for "5b-'" read 5B- column 7, line 51, for "-(Z-diethylaminoethoxy) 55- read (Z-diethylaminoethoxy) SB- line 63, for "30c-", in italics, read 3 1- in italics; column 8, line 40, for

"15 w" read 5 0L- column 9, line 29, after "hydrochloride" insert a semicolon; line 33, after "chloride" insert a semicolon; same column 9, line 60, for "3 6- (2-" read 3B- (2- column 12 line 72, for "(S-diethylaminopropoxy) read (fa-dimethylaminopropoxy)- column 13, line 43, for "pregene" read pregnene line 48, for "-(S-diethylaminopropxy) read (3-diethylaminopropoxy) column 14, line 7, for "3M2", in italics, read 3a-(2- in italics; column. 16, line 68, for "3OL(3-" read Sa- (3- column 17, line 29, for "20 ethylene" read 20-ethylene line 40, for "5-grams" read 5 grams lines 48 and 50, for "20 ethylene", each occurrence, read ZED-ethylene same column 17, line 52, for "fixe" read five column 19 line 15 for "3 B- (2" read 3 B- (3- column 20 line 3, for "3 6- (dimethylaminoethoxy) read 3 B- [2-dimethylaminoethoxy) Signed and sealed this 7th day of December 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J, BRENNER Attesting Officer Commissioner of Patents 

1. STEROID COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULAE: 